This proposal is designed to explore the mechanisms whereby several agents or conditions damage the kidney; how renal function is altered in response to these pathological processes; and how we can lessen the renal damage produced by these conditions by the use of drugs or other agents. Three major groups of experiments are proposed. In the first, we will assess the effects of administering the commonly used antimicrobial agent gentamicin. This drug is one of the most potent agents available for treating certain types of gram-negative infections. Unfortunately, its use frequently leads to impaired renal function. The object of these studies will be to determine how gentamicin damages the kidney, which patients are at highest risk from its nephrotoxic effects, and how we can decrease its toxicity. In the second group of experiments we will study the drug amphotericin. This drug is currently our most effective antifungal agent; its use, however, must frequently be discontinued because of renal damage before the desired antifungal effect is achieved. We will study the mechanisms by which this drug damages the kidney with particular attention to its effects on cell membranes. The third group of experiments will exmaine the role played by the potent, locally acting hormones, prostaglandins and thromboxanes in the kidney that is damaged by obstruction to the urinary tract and the extent to which these compounds interact with the renin-angiotensin system in altering renal function in hydronephrosis. These studies will utilize a combination of both physiological and morphological techniques. The physiological techniques to be utilized include: renal clearance and micropuncture studies, use of the isolated perfused rat kidney, the isolated perfused rabbit tubule, the metabolism of arachidonic acid in platelets and kidneys, and the use of radioactive microspheres and silicone rubber injections to study the renal vasculature. The morphological techniques to be utilized include the use of light and electron microscopy (including the use of routine transmission, scanning, and freeze fracture techniques).